Corresponding Author

In this issue of JACC: Cardiovascular Interventions, Seeger et al. (1) report on the highly relevant impacts of atrial fibrillation (AF) and oral anticoagulation (OAC) strategy after transcatheter aortic valve replacement (TAVR). AF is present in approximately one-third of patients undergoing TAVR (2) and has been shown to be independently associated with late cardiovascular morbidity and mortality, driven by an increased risk for stroke and bleeding relating to OAC. Thus, 1-year mortality of patients in AF in the PARTNER (Placement of Aortic Transcatheter Valves) 1B trial was doubled (26.2%) compared with patients in sinus rhythm (12.9%) and quadrupled (48.7%) if these patients experienced major bleeding complications within the first year of follow-up (3). Similar to previous reports, Seeger et al. show that TAVR patients with AF have a doubling of mortality (19.1% vs. 7.8%, p < 0.01) and increased life-threatening bleeding (4.4% vs. 0.9%, p < 0.01) compared with patients in sinus rhythm at 1 year after the procedure.

Because the TAVR population is typically older and frail, with multiple comorbidities, it can be a challenge to find a balance between prevention of thromboembolic events and avoidance of major bleeding. This is problematic in TAVR patients with known AF, as these patients have an indication for OAC therapy, in the form of either vitamin K antagonists (VKAs) or 1 of the novel oral anticoagulant agents, in combination with antiplatelet therapy for 3 to 6 months according to current practice and guidelines (4). However, recent data indicate that VKAs alone are as efficient and safe as VKAs in combination with antiplatelet therapy after TAVR (5). Indeed, after a median follow-up period of 13 months, the risk for stroke, major adverse cardiac events, or death was similar, with a doubling in major or life-threatening bleeding in patients who received VKAs in combination with single-antiplatelet therapy (SAPT) or dual-antiplatelet therapy (DAPT), similar findings to the WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial (6).

OAC has been associated with a lower rate of structural valve deterioration after TAVR (7) and with better outcomes after surgical aortic valve replacement (8). Moreover, with the recent reports and concerns regarding subclinical leaflet thrombosis in bioprosthetic aortic valves, the value of OAC has been reemphasized (9). Although it has been speculated that leaflet thrombosis and reduced motion may be related to thromboembolic events and reduced leaflet durability, the clinical impact of these abnormalities is still unclear. However, it seems that anticoagulation protects against leaflet thrombosis and may also resolve it. The GALILEO (Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) 4DCT substudy (NCT02833948) (n = 300) will evaluate whether a rivaroxaban-based strategy, following successful TAVR, compared with an antiplatelet-based strategy is superior in reducing subclinical valve leaflet thickening and motion abnormalities, as detected by 4-dimensional computed tomography.

Because avoidance of bleeding related to anticoagulation is of utmost importance, the question is whether novel oral anticoagulant agents may replace VKAs when an indication for OAC exists after TAVR. In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (10), apixaban was shown to be superior to VKAs in patients with AF in preventing thromboembolic events, at a lower rate of bleeding events. Intuitively, apixaban may be a preferred OAC in this older population, often with impaired renal function, but it has not previously been evaluated in patients with AF post-TAVR. Seeger et al. (1) evaluated for the first time the safety and efficacy of apixaban compared with VKAs in patients with AF after TAVR in 617 patients. Despite demonstrating previously comparable results compared with warfarin in a subgroup analysis of ARISTOTLE in patients with valvular disease (11), there was a tendency toward a lower stroke rate with apixaban compared with a VKA (2.1% vs. 5.3%, p = 0.17) with a significant reduction in bleeding rate in the apixaban group compared with the warfarin group (3.5% vs. 5.3%, p < 0.01) in this study.

Despite the reduction of bleeding shown with apixaban in this study, should an alternative to OAC in patients with AF post-TAVR be explored? Recently, left atrial appendage occlusion (LAAO) has been proposed as an alternative nonpharmacological treatment for stroke prevention in patients with AF with increased bleeding risk (12). LAAO to prevent atrial thrombosis has the potential to become the preferred strategy to prevent cerebrovascular events in patients with AF with contraindications to OAC therapy or at high bleeding risk, criteria that many TAVR patients fulfill. Attinger-Toller et al. (13) studied this hypothesis with simultaneous TAVR and LAAO in 1 clinical setting in 52 patients. After a mean follow-up period of 9.4 months, the investigators showed that TAVR and LAAO can be combined safely, with no adverse procedural outcomes. LAAO may be particularly attractive in patients with AF who undergo coronary revascularization with the use of drug-eluting stents prior to TAVR, because many of these patients will be committed on triple therapy with aspirin, clopidogrel, and oral anticoagulant agents (14). There is currently no randomized controlled trial comparing the outcomes of OAC and LAAO post-TAVR.

This study raises as well the ongoing debate on what is the best and optimal antithrombotic regimen in patients post-TAVR, regardless of whether they are in sinus rhythm or AF. This was reflected in a German registry of 1,450 patients showing that 7% of patients received aspirin or clopidogrel monotherapy, 11% received aspirin or clopidogrel with OACs, 66% of patients received DAPT, and 16% received triple therapy (15). In the study by Seeger et al. (1), 66% of patients were on SAPT and 34% on DAPT, although it has been reported that DAPT is associated with higher bleeding risk than SAPT (16). In concordance with this, a shortened period of DAPT of 1 month or SAPT alone after TAVR has been found to produce a similar rate of thromboembolic events and a trend toward a decrease in bleeding risks (5,17).

Consequently, what are the optimal treatment strategy and duration for an ideal balance between efficacy and bleeding? Several ongoing studies may help define these important questions (Table 1).

Different strategies are currently being investigated in patients with sinus rhythm:

1. The ARTE (Aspirin Versus Aspirin Clopidogrel Following Transcatheter Aortic Valve Implantation) study (NCT01559298) (n = 155) is a randomized study of 300 patients not on OAC who will be treated after TAVR with a combination of aspirin for at least 6 months and clopidogrel for 3 months or SAPT therapy with aspirin alone for at least 6 months.

2. Cohort A of the POPULAR-TAVI (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation) study (NCT02247128) (n = 1,010) is also a randomized study of 1,010 patients not on OAC who will be treated after TAVR with either clopidogrel 75 mg for 3 months or clopidogrel 75 mg for 3 months plus aspirin 100 mg for a year.

3. The GALILEO trial (NCT02556203) (n = 1,520) will assess whether a rivaroxaban-based anticoagulation strategy compared with an antiplatelet therapy–based strategy is superior in reducing death or thromboembolic events after TAVR. However, patients with histories of AF are excluded from GALILEO.

4. The AUREA (Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI) study (NCT01642134) (n = 124) is comparing the fixed combination of aspirin 80 mg/day and clopidogrel 75 mg/day versus OAC with acenocoumarol in patients with no indication for OAC, with respect to the occurrence of thromboembolic cerebrovascular events by magnetic resonance imaging at 3 months.

Different strategies are currently being investigated in patients with AF:

1. The AVATAR (Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions) study (NCT02735902) (n = 170) aims to demonstrate that single–oral anticoagulant therapy is superior to a combination of OAC and SAPT with respect to a net clinical benefit endpoint at 1 year.

2. Cohort B of the POPULAR-TAVI study (NCT02247128) (n = 1,010) is also a randomized study of 1,010 patients, in which patients with AF are randomized to either OAC monotherapy or OAC plus clopidogrel 75 mg for 3 months.

3. The ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial (NCT02664649) (n = 1,509) comprises a broader spectrum of TAVR patients (i.e., those with and without AF) to compare apixaban (5 mg twice daily or 2.5 mg twice daily) versus standard of care (VKAs in patients with indications for OAC or SAPT or DAPT in patients with no indication for OAC). The primary endpoint of ATLANTIS is the composite of death, myocardial infarction, systemic emboli, intracardiac or bioprosthetic thrombus, or major bleeding at 1 year.

A wealth of information will be uncovered from this potpourri of trials in the next few years, and one can foresee a change in the way we approach and manage patients after TAVR, both those with AF and those in sinus rhythm.

Footnotes

↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.

Dr. Søndergaard has received research grants from Medtronic, St. Jude Medical, Boston Scientific, Symetis, and Edwards Lifesciences; and is a proctor for Medtronic, St. Jude Medical, Boston Scientific, and Symetis. Dr. Sawaya has reported that he has no relationships relevant to the contents of this paper to disclose.

(2013) Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet381:1107–1115.

(2015) Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation132:624–632.